Polyglutamine neurodegenerative diseases are a devastating family of inherited disorders that include Huntington Disease and spinobulbar muscular atrophy (SBMA). Long-term goals of this project are to identify molecular mechanisms of polyglutamine neurodegenerative disease, to determine specific therapeutic targets, and to develop mechanism-based therapies. Previous work demonstrated that Y-27632, an inhibitor of the rho-associated kinase p160ROCK, reduced polyglutamine aggregation and toxicity in cell and Drosophila models. Aim 1: Identify and characterize novel regulatory pathways and target molecules. We will complete a screen of a library of biologically active small molecules. We will also analyze hits from two prior screens of biologically active compounds. Results will be analyzed in a systematic fashion using a combination of genetic and pharmacologic approaches to determine new pathways of potential significance. Aim 2: Determine the molecular mechanism by which p160ROCK signaling influences polyglutamine aggregation and toxicity. The role of specific components of the p160ROCK signaling pathway will be tested in Drosophila. The molecular basis of polyglutamine protein association with actin will be tested, and its role in modulating polyglutamine aggregation determined. Aim 3: Test the activity of Y-27632 in preventing neurodegeneration in vivo. Bioactivity of Y-27632 in brain, and systemic toxicity shall be determined in order to plan an appropriate dosing regimen. Y-27632 inhibition of polyglutamine-dependent pathology in vivo shall be tested using a variety of behavior, rotarod, pathological and biochemical analyses in the R6/2 mouse model of HD.